The present invention relates to compounds, compositions and methods useful in the treatment or prevention of conditions and disorders associated with eating behavior, energy homeostasis and anxiety.
G-protein coupled receptors play important roles in diverse signaling processes, including those involved with sensory and hormonal signal transduction. Eating disorders, which represent a major health concern throughout the world, have been linked to GPCR regulation. On the one hand, disorders such as obesity, the excess deposition of fat in the subcutaneous tissues, manifest themselves by an increase in body weight. Individuals who are obese often have, or are susceptible to, medical abnormalities including respiratory difficulties, cardiovascular disease, diabetes and hypertension. On the other hand, disorders like cachexia, the general lack of nutrition and wasting associated with chronic disease and/or emotional disturbance, are associated with a decrease in body weight.
The neuropeptide melanin-concentrating hormone (MCH), a cyclic hypothalamic peptide involved in the regulation of several functions in the brain, has previously been found to be a major regulator of eating behavior and energy homeostasis. It has previously been determined that MCH is the natural ligand for the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). Subsequent to this determination, SLC-1, which is sequentially homologous to the somatostatin receptors, is frequently referred to as melanin-concentrating hormone receptor (MCH receptor, MCHR or MCHR1) (see Chambers et al., Nature 400:261-65 (1999); Saito et al., Nature 400:265-69 (1999); and Saito et al., TEM 11(8):299-303 (2000)).
Compelling evidence exists that MCH is involved in regulation of eating behavior. First, intracerebral administration of MCH in rats resulted in stimulation of feeding. Next, mRNA corresponding to the MCH precursor is up-regulated in the hypothalamus of genetically obese mice and of fasted animals. Finally, mice deficient in MCH are leaner and have a decreased food intake relative to normal mice. MCH is believed to exert its activity by binding to MCHR, resulting in the mobilization of intracellular calcium and a concomitant reduction in cAMP levels (see Chambers et al., Nature 400:261-65 (1999); Shimada et al. Nature 396:670-74 (1998)). MCH also activates inwardly rectifying potassium channels, and MCHR has been found to interact with both Gai protein and Gaq protein (Saito et al., TEM 11(8):299-303 (2000)). Moreover, analysis of the tissue localization of MCHR indicates that it is expressed in those regions of the brain involved in olfactory learning and reinforcement. The cumulative data suggest that modulators of MCHR should have an effect on neuronal regulation of food intake (see Saito et al., Nature 400:265-69 (1999)).
MCH has been shown to modulate behaviors other than feeding, such as anxiety (Gonzales et al. (1996) Peptides 17:171-177; Monzon et al. (1999) Physiol. Behav. 67:813-817).
The identification of MCHR modulators is useful for the study of physiological processes mediated by MCHR and the development of therapeutic agents for the treatment or prevention of conditions and disorders associated with weight regulation, learning, anxiety and other neuronal-related functions.
The present invention provides fused heterocyclic compounds and compositions, and methods of use thereof to treat or prevent conditions and disorders mediated by MCHR. In particular, the present invention provides compounds, compositions and methods for treating or preventing conditions and disorders associated with eating behavior, energy homeostasis and anxiety.
The compounds provided herein have the formula (I): 
wherein
L is a bond or (C1-C4)alkylene;
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, CO2R13, SO2R13, C(O)NR13R14, SO2NR13R14 and (C1-C4)alkylene-CO2R13;
optionally, R and Rxe2x80x2 may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
Rxe2x80x3 is hydrogen or (C1-C9)alkyl;
each R1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR5, xe2x80x94SR5, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94C(O)R5, xe2x80x94CO2R5, xe2x80x94C(O)NR5R6, xe2x80x94N(R6)C(O)R5, xe2x80x94N(R6)CO2R5, xe2x80x94N(R7)C(O)NR5R6, xe2x80x94S(O)mNR5R6, xe2x80x94S(O)mR5, xe2x80x94CN and xe2x80x94N(R6)S(O)mR5;
R2 is selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR8, xe2x80x94SR8, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR8R9, xe2x95x90O, xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94C(O)NR8R9, xe2x80x94N(R9)C(O)R8, xe2x80x94N(R9)CO2R8, xe2x80x94N(R10)C(O)NR8R9, xe2x80x94S(O)mNR8R9, xe2x80x94S(O)mR8, xe2x80x94CN and xe2x80x94N(R9)S(O)mR8;
R4 is selected from the group consisting of hydrogen xe2x80x94OR11, xe2x80x94C(O)R11, xe2x80x94CO2R11, xe2x80x94C(O)NR11R12, xe2x80x94CN, (C1-C4)alkyl and aryl;
R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R16 and R17 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, hetero(C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
optionally, when two R groups selected from the group consisting of R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2.
Also provided herein are compounds of formula (II): 
wherein
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, CO2R13, SO2R13, C(O)NR13R14, SO2NR13R4 and (C1-C4)alkylene-CO2R13;
Rxe2x80x3 is hydrogen or (C1-C8)alkyl;
each R1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR5, xe2x80x94SR5, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94C(O)R5, xe2x80x94CO2R5, xe2x80x94C(O)NR5R6, xe2x80x94N(R6)C(O)R5, xe2x80x94N(R6)CO2R5, xe2x80x94N(R7)C(O)NR5R6, xe2x80x94S(O)mNR5R6, xe2x80x94S(O)mR5, xe2x80x94CN and xe2x80x94N(R6)S(O)mR5;
R2 is selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR8, xe2x80x94SR8, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR8R9, xe2x95x90O, xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94C(O)NR8R9, xe2x80x94N(R9)C(O)R8, xe2x80x94N(R9)CO2R8, xe2x80x94N(R10)C(O)NR8R9, xe2x80x94S(O)mNR8R9, xe2x80x94S(O)mR8, xe2x80x94CN and xe2x80x94N(R9)S(O)mR8;
R4 is selected from the group consisting of hydrogen xe2x80x94OR1, xe2x80x94C(O)R11, xe2x80x94CO2R11, xe2x80x94C(O)NR11R12, xe2x80x94CN, (C1-C4)alkyl and aryl;
R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, hetero(C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
optionally, when two R groups selected from the group consisting of R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2; and
the subscript p is an integer of from 1 to 4.
Also provided herein are compounds of formula (III): 
wherein
R and Rxe2x80x2 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, CO2R13, SO2R13, C(O)NR13R14, SO2NR13R14 and (C1-C4)alkylene-CO2R13;
optionally, R and Rxe2x80x2 may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
Rxe2x80x3 is hydrogen or (C1-C8)alkyl;
each R1 is independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR5, xe2x80x94SR5, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR5R6, xe2x80x94C(O)R5, xe2x80x94CO2R5, xe2x80x94C(O)NR5R6, xe2x80x94N(R6)C(O)R5, xe2x80x94N(R6)CO2R5, xe2x80x94N(R7)C(O)NR5R6, xe2x80x94S(O)mNR5R6xe2x80x94S(O)mR5, xe2x80x94CN and xe2x80x94N(R6)S(O)mR5;
R2 is selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, xe2x80x94OR8, xe2x80x94SR8, fluoro(C1-C4)alkoxy, aryl, aryl(C1-C4)alkyl, xe2x80x94NO2, xe2x80x94NR8R9, xe2x95x90O, xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94C(O)NR8R9, xe2x80x94N(R9)C(O)R8, xe2x80x94N(R9)CO2R8, xe2x80x94N(R10)C(O)NR8R9, xe2x80x94S(O)mNR8R9, xe2x80x94S(O)mR8, xe2x80x94CN and xe2x80x94N(R9)S(O)mR8;
R4 is selected from the group consisting of hydrogen xe2x80x94OR11, xe2x80x94C(O)R11, xe2x80x94CO2R11, xe2x80x94C(O)NR11R12, xe2x80x94CN, (C1-C4)alkyl and aryl;
R5, R6, R7, R8, R9, R16 and R17 are independently selected from the group consisting of hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C4)alkyl, hetero(C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
optionally, when two R groups selected from the group consisting of R5, R6, R7, R8, R9, R16 and R17 are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2;
the subscript n is 0, 1 or 2; and
the subscript p is an integer of from 1 to 4.
The compounds provided in the above formula are meant to include all pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.
The pharmaceutical compositions provided herein comprise a pharmaceutically acceptable carrier or excipient in combination with a compound of formula I.
Methods for treating or preventing a condition or disorder selected from the group consisting of obesity, an eating disorder, an anxiety disorder and a mood disorder are provided herein. The methods comprise administering to a subject in need thereof a therapeutically effective amount of one of the foregoing compounds or pharmaceutical compositions.
Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following description and claims.